The Autoimmune Manifestations in Patients with Genetic Defects in the B Cell Development and Differentiation Stages

Abstract

Purpose: Primary B cell defects manifesting as predominantly antibody deficiencies result from variable inborn errors of the B cell lineage and their development, including impairments in early bone marrow development, class switch recombination (CSR), or terminal B cell differentiation. In this study, we aimed to investigate autoimmunity in monogenic patients with B cell development and differentiation defects.

Methods: Patients with known genetic defects in the B cell development and differentiation were recruited from the Iranian inborn errors of immunity registry.

Results: A total of 393 patients with a known genetic defect in the B cell development and differentiation (257 males; 65.4%) with a median age of 12 (6-20) years were enrolled in this study. After categorizing patients, 109 patients had intrinsic B cell defects. More than half of the patients had defects in one of the ATM (85 patients), BTK (76 patients), LRBA (34 patients), and DOCK8 (33 patients) genes. Fifteen patients (3.8%) showed autoimmune complications as their first manifestation. During the course of the disease, autoimmunity was reported in 81 (20.6%) patients at a median age of 4 (2-7) years, among which 65 patients had mixed intrinsic and extrinsic and 16 had intrinsic B cell defects. The comparison between patients with the mentioned four main gene defects showed that the patient group with LRBA defect had a significantly higher frequency of autoimmunity compared to those with other gene defects. Based on the B cell defect stage, 13% of patients with early B cell defect, 17% of patients with CSR defect, and 40% of patients who had terminal B cell defect presented at least one type of autoimmunity.

Conclusion: Our results demonstrated that gene mutations involved in human B cell terminal stage development mainly LRBA gene defect have the highest association with autoimmunity.

Keywords: Antibody deficiency; Autoimmunity; B cell; Class switch recombination; Inborn errors of immunity; Primary immunodeficiency.

Fig. 1

First presentation in 393 patients with primary B cell defects. FTT failure to thrive. Others included presentations such as convulsion, arthritis, faintness, facial nerve palsy, skin lesion, imbalance, stagger, coughing, inguinal hernia, gastrointestinal bleeding, jaundice and anorexia

Fig. 2

The spectrum of clinical diagnoses in B cell defective patients in early stage (A, n = 138), CSR stage (B, n = 140), and terminal stage (C, n = 115) of B cell developmental defect. CVID common variable immunodeficiency, HIgM hyper-IgM syndrome, HIES hyper-IgE syndrome, MSMDs Mendelian susceptibility to mycobacterial diseases, SIgAD selective IgA deficiency, WAS Wiskott-Aldrich syndrome, AT ataxia-telangiectasia, SCID severe combined immunodeficiency, SAD specific antibody deficiency, CID combined immunodeficiency, CMCC chronic mucocutaneous candidiasis, XLP X-linked lymphoproliferative, ALPS autoimmune lymphoproliferative syndrome, HLH hemophagocytic lymphohistiocytosis

Fig. 3

The spectrum of clinical diagnoses in B cell defective patients with autoimmunity (A, n = 81) and without autoimmunity (B, n = 312). CVID common variable immunodeficiency, HIgM hyper-IgM syndrome, HIES hyper-IgE syndrome, MSMDs Mendelian susceptibility to mycobacterial diseases, SIgAD selective IgA deficiency, WAS Wiskott-Aldrich syndrome, AT ataxia-telangiectasia, SCID severe combined immunodeficiency, SAD specific antibody deficiency, CID combined immunodeficiency, CMCC chronic mucocutaneous candidiasis

Fig. 4

Kaplan–Meier survival analysis in patients with primary B cell defects. A Based on the B cell defect stage (early stage with 138 patients, CSR stage with 140 patients, and terminal stage patients with 115 patients). B Based on the autoimmunity presence (81 patients with autoimmunity and 312 without autoimmunity)